Lars Forsberg – The role of loss of chromosome Y (LOY) in human health and disease

Mutations arise in every cell division and as a consequence, no two cells of an adult human body should be genetically identical. Mutations that arise during life-time are called post-zygotic (PZ) and they accumulate within the body with age. The overall interest in my group is to understand how such PZ mutations influence human phenotypes and risk for various diseases.

Many PZ mutations are neutral while others can compromise the biological functions of the affected cells. In some instances, the mutated cells transform into cancer but they can also be connected with other disease conditions. For example, we have discovered that men with mosaic loss of chromosome Y (LOY) in peripheral blood cells have a shorter survival and increased risk for cancer in the entire body as well as an increased risk for Alzheimer’s disease.

We have also shown that LOY is associated with age and can be induced by smoking. Men in developed countries lives on average about 6 years shorter compared to women. As a male-specific genetic risk factor LOY could help explain the observed sex-difference in longevity and risk for various diseases.

How can a mutation in blood cells influence disease processes in other organs?

This is a central question in our ongoing research. One hypothesis is that the immune cells in blood, that normally fight disease processes and eliminate diseased cells in all parts of the body, have a disrupted function after losing the Y chromosome.

We and others have now established that LOY in blood cells is associated with various diseases in other organs. Our ongoing research is focusing on the functional consequences of LOY to better understand what happens in cells after they have lost the Y chromosome. We are also performing LOY-analyses of sorted blood cells with the aim to improve the clinical utility of LOY as a biomarker.

Mosaic loss of chromosome Y (LOY) is the most common human somatic mutation and recent studies have found that men with LOY in blood leukocytes have an increased risk for outcomes such as all-cause mortality, non-hematological cancer, Alzheimer’s disease (AD) and cardiovascular disease (CVD).